Degeneration of the intervertebral disc is a common problem in the adult population, arid leads to significant morbidity and health care expenditure. Current treatment options are limited to conservative care or a relatively few surgical procedures, all of which have less than optimal outcomes. With recent advances in minimally-invasive surgical procedures and biological methods for guiding tissue healing, the prospect of biologic disc repair has gained significant clinical interest. Current efforts have focused on stimulating disc cells with growth factors, transfecting disc cells using gene therapy procedures, or transplanting autologous disc cells that have been expanded ex vivo. These approaches are limited due to the inherent low cellularity of degenerated discs (limiting the efficacy of in situ growth factor or gene therapy), and graft procurement and harvest site morbidity (limiting the practicality of autologous cell transplantation). We hypothesize that mesenchymal stem cells (MSCs) derived from bone marrow have the capacity to differentiate appropriately within the disc environment and thereby initiate a significant repair response. MSCs have the advantage of being readily available (from bone marrow) and can differentiate into a number of relevant cell types. To test the feasibility of using MSCs for disc repair, we propose two specific aims. First, we will characterize how human MSCs (at two different differentiation stages) respond to bioreactor culture under conditions that mimic the in vivo disc environment (low pH, low oxygen concentration, high pressure). We will compare the response of these MSCs to disc cells cultured under the same conditions. In aim 2, the MSC stage that most closely matches disc cells will be injected into degenerated athymic rat-tail discs. The response of the tail discs tc cell injection will be monitored at various time points up to 28 days by assessing histology, matrix production, and biomechanical properties. We anticipate that the results of this research will establish feasibility of using MSCs to guide disc remodeling and repair. Upon successful completion, we will extend this work to a large animal model of disc degeneration where surgical, biological, and mechanical challenges more closely match those anticipated with human use. [unreadable] [unreadable]